26 January 2006. In the December issue of the journal Psychiatric Services, Mark Ragins, of Village Integrated Services Agency in Long Beach, California, wrote an editorial on the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) report in the September 19, 2005, issue of the New England Journal of Medicine (see SRF related news story and commentary). He suggested that the high drug discontinuation rates reflected problems with the treatment the patients received while in the study, and concluded, "I don't think the CATIE study should be a wake-up call to 'clinicians, patients, families, and policymakers.' I think it should be a wake-up call to researchers." In the January issue of Psychiatric Services, study authors Jeff Lieberman of Columbia University and John Hsiao of the National Institute of Mental Health respond to Ragins's letter, explaining aspects of the study protocol and conclusions, and pointing out that the New England Journal of Medicine report "is but an initial installment from a remarkably rich data set." (See, e.g., Goff et al., 2005; Miller et al., 2005; McEvoy et al., 2005; and Meyer et al., 2005). Access to both of these articles in Psychiatric Services is free.—Hakon Heimer.

In the comment about the CATIE study, Dr. Ragins described...
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In the comment about the CATIE study, Dr. Ragins described a series of variables, such as the attitudes of the patients toward the medications, that were not included in the discussion of Dr. Lieberman's study in this first CATIE study version. The author of the cited commentary summarized an old rivalry between the "clinical" versus the "scientific and technical" research approach in the field of mental health. I think that, at this time in the development of science, this old opposition (between clinicians and researchers) should not exist anymore.

I believe that the results of the CATIE study indirectly support the core principle of treatment, that is, it should be comprehensive, using a biopsychosocial approach. The large number of dropouts is but one example of the limitations of relying on antipsychotic medication alone in the treatment of schizophrenia. We know that psychosocial treatments enhance compliance and overall outcome. See, for example, the study that my colleagues and I conducted on relapse prevention in schizophrenia, which had a small number of dropouts over 18 months (Herz et al., 2000).

This perspective piece is right on target. Little progress...
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This perspective piece is right on target. Little progress has been made since the introduction of chlorpromazine in pharmacotherapy of schizophrenia. Insel and Scolnick have been critical of the lack of progress, and have provided an NIMH focus on discovery of drugs with novel mechanisms. Here they note severity as measured in public health burden (disability and mortality), show how the shortfall in drug development compares with cardiovascular disease, and discuss reasons for the lack of progress.

Take home messages include the following:

1. Shift the focus of neurobiologic study away from the investigation of the biology of current drugs and toward disease etiology and pathophysiology. Prepare to develop drugs based on molecular pathology rather than knowledge of mechanisms of already discovered drugs.

It is easy to agree, but changing the culture of discovery may be difficult. There is a better financial risk/benefit profile to developing "me, too" drugs than the high risk involved with novel mechanisms. It is also important that our field does not have a sense of urgency in advancing therapeutics for schizophrenia. There is nothing similar to the state of agitation and impatience associated with developing drugs for AIDS, for example.

I think the NIMH initiative identifying specific domains for drug development (cognition impairments with the MATRICS project, and negative symptoms next in line) gives emphasis to areas of unmet treatment needs, and increases the ease of translation of neuroscience and animal models into pathologic models.

There are a number of studies suggesting that a subgroup of patients do very well off medication (see Bola, 2005), but it has been very difficult to define this subgroup, except that good prognosis factors predict good outcome groups. Most importantly, the available data do not indicate how the patients doing well off medication would be doing if they were on medication. The adverse effects of drugs would be avoided, and this is non-trivial for neuroleptic effects of many first-generation antipsychotics and for metabolic effects of many second-generation antipsychotics. The current paper does not address risk/benefit issues, but does report benefit to stable patients continuing antipsychotic drug treatment. This is important, and finding the drug and dose which minimize adverse effects is critical.

This article states very well the divergent approaches found between psychiatric research and non-psychiatric research. In many well-crafted scientific research reports/articles there tends to be a small sentence that usually goes: "This finding may lead to better treatments." We clearly know that it won't lead to more efficacious treatments unless we change the research strategy as outlined in the article.

Although the article covers the societal costs well, it fails to mention that less that 30 percent of NIMH funding is dedicated to serious neuropsychiatric disorders that take up at least 70 percent of total direct treatment costs of all psychiatric disorders. NIAID does not spend the majority of its funds researching the common cold, but instead puts HIV and other infectious diseases at the clear forefront of the research agenda.

Also not stated is the fact that the two most effective medications for bipolar disorder and schizophrenia were accidental discoveries in 1949 (lithium carbonate) and 1959 (clozapine). A similar case exists for antidepressant drugs. Although it took approximately 20 years for lithium and 30 years for clozapine to be brought to market on a widespread basis, psychiatric research in the last several decades has failed to produce anything more efficacious than these 57-year-old and 47-year-old discoveries.

Continually studying a 47-year-old accident (clozapine) may yield useful information as to how to develop more efficacious drugs, but this strategy alone will not help the many patients currently suffering by not being able to work productively, live somewhat independently, socialize satisfactorily, or maintain optimal health. The bridge must be built between the lab and the community.